美国弗里德曼大脑研究所Anne Schaefer小组揭示了淋巴样基因表达支持小胶质细胞的神经保护功能。相关论文于2025年11月5日发表于国际顶尖学术期刊《自然》杂志上。

本研究表明，小胶质细胞的保护功能是由转录因子PU.1控制的，当小胶质细胞与斑块接触后，PU.1会下调。降低小胶质细胞中PU.1的表达可降低小鼠淀粉样蛋白疾病病理的严重程度，并与免疫调节淋巴样受体蛋白的表达有关，特别是CD28，这是一种对T细胞活化至关重要的表面受体。CD28的小胶质细胞特异性缺陷，由一小部分斑块相关的PU.1^low小胶质细胞表达，促进广泛的炎性小胶质细胞状态，与淀粉样斑块负荷增加有关。他们的研究结果表明，表达PU.1^low CD28的小胶质细胞可能作为抑制性小胶质细胞，通过降低神经炎症的严重程度来减缓阿尔茨海默病的进展。CD28和潜在的其他淋巴样共刺激和共抑制受体蛋白在控制AD小胶质细胞反应中的作用，指出了通过促进小胶质细胞的保护性功能来治疗疾病的可能的免疫治疗方法。

据介绍，小胶质细胞是大脑的先天免疫细胞，在阿尔茨海默病（AD）的进展中起着决定性的作用。AD患者的小胶质细胞对淀粉样斑块的反应从神经保护到神经毒性不等。

附：英文原文

Title: Lymphoid gene expression supports neuroprotective microglia function

Author: Ayata, Pinar, Crowley, Jessica M., Challman, Matthew F., Sahasrabuddhe, Vinaya, Gratuze, Maud, Werneburg, Sebastian, Ribeiro, Diogo, Hays, Emma C., Durn-Laforet, Violeta, Faust, Travis E., Hwang, Philip, Mendes Lopes, Francisco, Nikopoulou, Chrysa, Buchholz, Sarah, Murphy, Robert E., Mei, Taoyu, Pimenova, Anna A., Romero-Molina, Carmen, Garretti, Francesca, Patel, Tulsi A., De Sanctis, Claudia, Ramirez Jimenez, Angie V., Crow, Megan, Weiss, Felix D., Ulrich, Jason D., Marcora, Edoardo, Murray, John W., Meissner, Felix, Beyer, Andreas, Hasson, Dan, Crary, John F., Schafer, Dorothy P., Holtzman, David M., Goate, Alison M., Tarakhovsky, Alexander, Schaefer, Anne

Issue&Volume: 2025-11-05

Abstract: Microglia, the innate immune cells of the brain, play a defining role in the progression of Alzheimer’s disease (AD)1. The microglial response to amyloid plaques in AD can range from neuroprotective to neurotoxic2. Here we show that the protective function of microglia is governed by the transcription factor PU.1, which becomes downregulated following microglial contact with plaques. Lowering PU.1 expression in microglia reduces the severity of amyloid disease pathology in mice and is linked to the expression of immunoregulatory lymphoid receptor proteins, particularly CD28, a surface receptor that is critical for T cell activation3,4. Microglia-specific deficiency in CD28, which is expressed by a small subset of plaque-associated PU.1low microglia, promotes a broad inflammatory microglial state that is associated with increased amyloid plaque load. Our findings indicate that PU.1low CD28-expressing microglia may operate as suppressive microglia that mitigate the progression of AD by reducing the severity of neuroinflammation. This role of CD28 and potentially other lymphoid co-stimulatory and co-inhibitory receptor proteins in governing microglial responses in AD points to possible immunotherapy approaches for treating the disease by promoting protective microglial functions.

DOI: 10.1038/s41586-025-09662-z

Source: https://www.nature.com/articles/s41586-025-09662-z